Stable cannabinoid formulations

ABSTRACT

The present invention is generally directed to substantially pure cannabidiol, stable cannabinoid pharmaceutical formulations, and methods of their use.

PRIORITY

This application is a divisional of U.S. application Ser. No.14/724,351, filed May 28, 2015, now U.S. Pat. No. 11,224,660, issuedJan. 18, 2022, which claims priority to U.S. Provisional PatentApplication Nos. 62/004,495, filed May 29, 2014, and 62/154,660, filedApr. 29, 2015. The entire contents of each application are incorporatedherein by reference.

FIELD OF THE INVENTION

The present invention is generally directed to substantially purecannabidiol, stable cannabinoid pharmaceutical formulations, and methodsof their use.

BACKGROUND

Cannabinoids are chemicals that are produced by Cannabis flowers.Cannabinoids imitate endogenous compounds in humans.

Cannabinoids include cannabinol, cannabidiol, dronabinol(delta-9-tetrahydrocannabinol), delta-8-tetrahydrocannabinol,11-hydroxy-tetrahydrocannabinol, 11-hydroxy-delta9-tetrahydrocannabinol,levonantradol, delta-11-tetrahydrocannabinol, tetrahydrocannabivarin,amandamide, nabilone, and acids and analogs thereof. It is now possibleto synthesize many cannabinoids in a laboratory thereby eliminating theneed to grow Cannabis for extraction of the compounds.

One cannabinoid, cannabidiol,(−)-trans-2-p-mentha-1,8-dien-3-yl-5-pentylresorcinol, isnon-psychoactive and has shown promise in treating numerous diseases anddisorders. Synthetic cannabidiol has the same structure as naturallyoccurring cannabidiol.

Commercially available cannabidiol is usually contaminated with delta9-tetrahydrocannabinol. The presence of delta-9-tetrahydrocannabinol canbe a concern because delta-9-tetrahydrocannabinol is regulated by theUnited States Drug Enforcement Administration as a Schedule I Drug.Having a higher Schedule number could result in easier access forpatients to cannabidiol treatments. Further,delta-9-tetrahydrocannabinol is a hallucinogen and patients receivingcannabidiol wish to avoid this undesirable side effect of thedelta-9-tetrahydrocannabinol contaminant. Therefore, there is a need fora substantially pure synthetically synthesized cannabidiol that does notcontain delta-9-tetrahydrocannabinol.

Cannnabinoids, including cannabidiol, may be suitable for the treatmentof diseases or disorders, or symptoms of diseases or disorders, such asDravet Syndrome, Lennox Gastaut Syndrome, mycolonic seizures, juvenilemycolonic epilepsy, refractory epilepsy, schizophrenia, juvenile spasms,West syndrome, refractory infantile spasms, infantile spasms, tubularsclerosis complex, brain tumors, neuropathic pain, Cannabis usedisorder, post-traumatic stress disorder, anxiety, early psychosis,Alzheimer's Disease autism, and withdrawal from opioids, cocaine,heroin, amphetamines, and nicotine.

Accordingly, there is a need for new stable cannabinoid formulations.There is also a need for substantially pure cannabidiol.

SUMMARY OF THE INVENTION

In one aspect, the present invention is directed to stablepharmaceutical formulations for oral administration comprising fromabout 0.1 to about 50% of a cannabinoid, from about 0.1 to about 40% ofa polyethylene glycol, from about 0.1 to about 50% of propylene glycol,and from about 0.1 to about 20% of water, wherein the formulation doesnot contain alcohol and the formulation has a pH of from about 5 toabout 8.

In another aspect, the present invention is directed to stablepharmaceutical formulations for oral administration comprising fromabout 0.1 to about 40% of a cannabinoid, from about 0.1 to about 25% ofa polyethylene glycol, from about 0.1 to about 40% of propylene glycol,optionally from about 0.1 to about 50% of water; and from about 0.1 toabout 70% of alcohol, wherein the formulation has a pH of from about 5to about 8.

In yet another aspect, the present invention is directed to stablepharmaceutical formulations for oral administration comprising fromabout 0.1 to about 40% of a cannabinoid and from about 10 to about 95%of a lipid.

In another aspect, the invention is directed to methods of using acannabinoid or substantially pure, synthetically synthesizedcannabidiol: to treat diseases or disorders, or symptoms of diseases ordisorders, such as Dravet Syndrome, Lennox Gastaut Syndrome, mycolonicseizures, juvenile mycolonic epilepsy, refractory epilepsy,schizophrenia, juvenile spasms, West syndrome, infantile spasms,refractory infantile spasms, tubular sclerosis complex, brain tumors,neuropathic pain, Cannabis use disorder, post-traumatic stress disorder,anxiety, early psychosis, Alzheimer's Disease, and autism; to assistwith withdrawal from opioids, cocaine, heroin, amphetamines andnicotine; and as an analgesic or to assist with handling of adverseemotional stimuli.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the results from the study detailed in Example 7 andillustrates the advantages of administration of substantially pure,synthetically synthesized, cannabidiol formulations for treatment ofneuropathic pain.

FIG. 2 shows the results from the study detailed in Example 9 andillustrates the advantages of administration of substantially pure,synthetically synthesized, cannabidiol formulations for treatment ofglioblastoma multiforme.

DETAILED DESCRIPTION

Applicant unexpectedly created new storage stable formulationscontaining cannabinoids. Applicant determined that a pH of from about 5to about 8 is critical for the formulations to remain stable, preferablyfrom about 6 to about 7. For example, as seen in Example 2 below, thealcohol-free formulations #AF3 and #AF4 exhibited excellent stabilityfor four weeks regardless of the temperature and humidity conditions.Further, in Example 4, Applicant unexpectedly found that the alcoholcontaining formulations #A7 and #A8 exhibited excellent stability for atleast 12 months regardless of the temperature and humidity conditions.Applicant also determined that an antioxidant is important to maintainstability during long-term storage. These results were not expectedbecause formulation science is incredibly difficult to predict and manyotherwise suitable formulations for pharmaceutical use are not stableduring storage.

As indicated above, Applicant created stable formulations with andwithout alcohol (see Examples 1 and 3). The formulations that do notcontain alcohol are especially suitable for administration to children.Further, the alcohol-free formulations are especially suitable forpatients in recovery from drug and alcohol addiction.

In addition, Applicant created stable formulations lipid formulations(see Example 5). These formulations were also unexpectedly stable duringstorage (see Example 6).

Further, Applicant unexpectedly found that substantially purecannabidiol formulations are especially suitable for treatment ofepilepsy (see Examples 8, 10 and 11), neuropathic pain (see Example 7and FIG. 1), and glioblastoma multiforme (see Example 9 and FIG. 2).

Alcohol-Free Formulations

In one embodiment, the present invention is directed to stablepharmaceutical formulation for oral administration comprising from about0.1 to about 50% of a cannabinoid, from about 0.1 to about 40% of apolyethylene glycol, from about 0.1 to about 50% of propylene glycol,and from about 0.1 to about 20% of water, wherein the formulation doesnot contain alcohol and the formulation has a pH of from about 5 toabout 8.

In a preferred embodiment, the formulations contain from about 1 toabout 40% of a cannabinoid. In more preferred embodiments, theformulations contain from about 5 to about 35%, from about 20 to about35% or from about 30 to 35% of a cannabinoid.

In yet another embodiment, the formulations contain a cannabinoidselected from group consisting of cannabinol, cannabidiol, dronabinol(delta-9-tetrahydrocannabinol), delta-8-tetrahydrocannabinol,11-hydroxy-tetrahydrocannabinol,11-hydroxy-delta-9-tetrahydrocannabinol, levonantradol,delta-11-tetrahydrocannabinol, tetrahydrocannabivarin, amandamide,nabilone, acids, analogs, and synthetic derivatives thereof. In apreferred embodiment, the cannabinoid is cannabidiol.

In a preferred embodiment, the formulations contain from about 1 toabout 40% of a cannabidiol. In more preferred embodiments, theformulations contain from about 5 to about 35%, from about 20 to about35% or from about 30 to 35% of a cannabidiol.

In yet another embodiment, the formulations contain cannabidiol that issubstantially pure and synthetically synthesized which has a purity ofgreater than 98%. In a more preferred embodiment, the cannabidiol isgreater than 99% pure. In an even more preferred embodiment, thecannabidiol is greater than 99.5% pure. In a most preferred embodiment,the cannabidiol formulation contains less than 0.3%delta-9-tetrahydrocannabinol.

In another embodiment, the formulations contain from about 0.001 toabout 1% of an antioxidant. In a preferred embodiment, the formulationscontain from about 0.01 to about 1% antioxidant. In a more preferredembodiment, the formulations contain from about 0.02 to about 0.5%antioxidant.

Suitable antioxidants include butylated hydroxyltoluene, butylatedhydroxyl anisole, alpha-tocopherol (Vitamin E), ascorbyl palmitate,ascorbic acid, sodium ascorbate, ethylenediamino tetraacetic acid,cysteine hydrochloride, citric acid, sodium citrate, sodium bisulfate,sodium metabisulfite, lecithin, propyl gallate, sodium sulfate,monothioglycerol and combinations thereof. In a preferred embodiment,the formulations contain alpha-tocopherol (Vitamin E), ascorbic acid,sodium ascorabte, ascobyl palminate or combinations thereof.

In another embodiment, the formulations contain from about 1 to about40% of a polyethylene glycol. In a preferred embodiment, theformulations contain from about 1 to about 35%, from about 5 to about35%, from about 20 to about 30%, or from about 25 to about 30%polyethylene glycol.

Suitable polyethylene glycols include low molecular weight polyethyleneglycols with an average molecular weight of between 200 and 10,000. Onepreferred polyethylene glycol that can be used is polyethylene glycol400.

In another embodiment, the formulations contain from about 1 to about40% of polyethylene glycol 400. In a preferred embodiment, theformulations contain from about 1 to about 35%, from about 5 to about35%, from about 20 to about 30%, or from about 25 to about 30%polyethylene glycol 400.

In another embodiment, the formulations contain from about 1 to about50% of propylene glycol. In a preferred embodiment, the formulationscontain from about 1 to about 40%, from about 5 to about 35%, from about20 to about 35%, or from about 30 to about 35% propylene glycol.

In a further embodiment, the formulations contain water. Theformulations can contain 0% water. If the formulations contain water,they can include from about 1 to about 15% water, from about 1 to about10% water, or from about 4 to about 8% water.

The pH of the formulations may be modified using any pharmaceuticallyacceptable means. Preferably the pH of the formulation is from about 5to about 8. In a more preferred embodiment, the pH of the formulationsis from about 6 to about 7. In a most preferred embodiment, the pH ofthe formulations is from about 6.2 to about 6.7.

The formulations of the present invention may also contain sweeteners,sweetener enhancers, preservatives, pH modifiers, and flavoring agents.

Suitable sweeteners include, but are not limited to, sucrose, aspartame,saccharin, dextrose, mannitol, xylitol, and combinations thereof.

If the formulations contain a sweetener, the formulations preferablycontain from about 0.001 to about 1% sweetener.

If the formulations contain a sweetness enhancer, the formulationspreferably contain from about 0.001 to about 1% sweetness enhancer.

Suitable sweetness enhancers include, but are not limited to, theammonium salt forms of crude and refined Glycyrrhizic Acid. Magnasweet®products (available from Mafco Worldwide Corporation, Magnasweet is aregistered trademark of Mafco Worldwide Corporation) use the ammoniumsalt forms of crude and refined Glycyrrhizic Acid. Glycyrrhizic Acid isalso available as a pure derivative in the sodium and potassium saltforms.

Suitable pH modifiers include, but are not limited to, hydrochloricacid, ascorbic acid, citric acid, sodium citrate, fumaric acid, sodiumhydroxide, sodium bicarbonate, sodium carbonate, ammonium carbonate, andcombinations thereof.

Suitable preservatives include, but are not limited to, methyl paraben,propyl paraben, benzyl alcohol, benzoic acid, sodium benzoate, sorbicacid, and combinations thereof.

Suitable flavoring agents include, but are not limited to, raspberry,peppermint oil, grape flavor, menthol, spearmint oil, citrus oil,cinnamon oil, strawberry flavor, cherry flavor, raspberry flavor, orangeoil, lemon oil, lemon mint flavor, fruit punch flavor, and combinationsthereof. In a preferred embodiment, the formulations contain strawberryflavor.

If the formulations contain a flavoring agent, the formulationspreferably contain from about 0.001 to about 1% flavoring agent. In amore preferred embodiment, the formulations contain from about 0.005 toabout 0.5% of the flavoring agent.

The formulations are suitable for oral, buccal, sublingual, inhalationor intravenous/intramuscular administration. Preferably, theformulations are liquids administered orally.

Formulations Containing Alcohol

In another embodiment, the invention is directed to stablepharmaceutical formulation for oral administration comprising from about0.1 to about 40% of a cannabinoid, from about 0.1 to about 25% of apolyethylene glycol, from about 0.1 to about 40% of propylene glycol,optionally from about 0.1 to about 50% of water, and from about 0.1 toabout 70% of alcohol, wherein the formulation has a pH of from about 5to about 8.

In a preferred embodiment, the formulations contain from about 1 toabout 35% of a cannabinoid. In a more preferred embodiment, theformulations contain from about 1 to about 15%, from about 5 to about12% or from about 7 to about 11% cannabinoid. Alternatively, theformulations may contain from about 20 to about 35% or from about 30 toabout 35% cannabinoid.

In yet another embodiment, the formulations contain a cannabinoidselected from group consisting of cannabinol, cannabidiol, dronabinol(delta-9-tetrahydrocannabinol), delta-8-tetrahydrocannabinol,11-hydroxy-tetrahydrocannabinol,11-hydroxy-delta-9-tetrahydrocannabinol, levonantradol,delta-11-tetrahydrocannabinol, tetrahydrocannabivarin, amandamide,nabilone, acids, analogs, and synthetic derivatives thereof. In apreferred embodiment, the cannabinoid is cannabidiol.

In a preferred embodiment, the formulations contain from about 1 toabout 35% of a cannabidiol. In a more preferred embodiment, theformulations contain from about 1 to about 15%, from about 5 to about12% or from about 7 to about 11% cannabidiol. Alternatively, theformulations may contain from about 20 to about 35% or from about 30 toabout 35% cannabidiol.

In yet another embodiment, the formulations contain cannabidiol that issubstantially pure and synthetically synthesized which has a purity ofgreater than 98%. In a more preferred embodiment, the cannabidiol isgreater than 99% pure. In an even more preferred embodiment, thecannabidiol is greater than 99.5% pure. In a most preferred embodiment,the cannabidiol formulation contains less than 0.3%delta-9-tetrahydrocannabinol.

In another embodiment, the formulations contain from about 0.001 toabout 1% of an antioxidant. In a preferred embodiment, the formulationscontain from about 0.01 to about 1% antioxidant. In a more preferredembodiment, the formulations contain from about 0.02 to about 0.5%antioxidant.

Suitable antioxidants include butylated hydroxyltoluene, butylatedhydroxyl anisole, alpha-tocopherol (Vitamin E), ascorbyl palmitate,ascorbic acid, sodium ascorbate, ethylenediamino tetraacetic acid,cysteine hydrochloride, citric acid, sodium citrate, sodium bisulfate,sodium metabisulfite, lecithin, propyl gallate, sodium sulfate, andcombinations thereof. In a preferred embodiment, the formulationscontain alpha-tocopherol (Vitamin E), ascorbic acid, sodium ascorabte,ascobyl palminate or combinations thereof.

In another embodiment, the formulations contain from about 1 to about20% of propylene glycol. In a preferred embodiment, the formulationscontain from about 1 to about 15% or from about 5 to about 10% propyleneglycol.

In an alternative embodiment, the formulations contain from about 20 toabout 50% of propylene glycol. In a preferred embodiment, theformulations contain from about 30 to about 40% or from about 30 toabout 35% propylene glycol.

In another embodiment, the formulations contain from about 1 to about20% of a polyethylene glycol. In a preferred embodiment, theformulations contain from about 1 to about 10% or from about 1 to about5% polyethylene glycol.

In an alternative embodiment, the formulations contain from about 10 toabout 20% of a polyethylene glycol. In a preferred alternativeembodiment, the formulations contain from about 15 to about 20%polyethylene glycol.

Suitable polyethylene glycols include low molecular weight polyethyleneglycols with an average molecular weight of between 200 and 10,000. Onepreferred polyethylene glycol that can be used is polyethylene glycol400.

In another embodiment, the formulations contain from about 1 to about20% of polyethylene glycol 400. In a preferred embodiment, theformulations contain from about 1 to about 10% or from about 1 to about5% polyethylene glycol 400.

In an alternative embodiment, the formulations contain from about 10 toabout 20% of polyethylene glycol 400. In a preferred alternativeembodiment, the formulations contain from about 15 to about 20%polyethylene glycol 400.

In a further embodiment, the formulations contain water. Theformulations can contain 0% water. If the formulations contain water,they can include from about 1 to about 40% water, from about 5 to about40% water, from about 10 to about 35% water or from about 25 to about35% water.

In yet another embodiment, the formulations contain from about 1 toabout 65% alcohol. In a preferred embodiment, the formulations containfrom about 10 to about 65%, from about 15 to about 60%, or from about 30to 55% alcohol.

In an alternative embodiment, the formulations contain from about 1 toabout 20% alcohol. In a preferred alternative embodiment, theformulations contain from about 1 to about 10% or from about 3 to about7% alcohol.

The pH of the formulations may be modified using any pharmaceuticallyacceptable means. Preferably the pH of the formulations is from about 6to about 7. In a more preferred embodiment, the pH of the formulationsis from about 6.2 to about 6.7.

The formulations of the present invention may also contain sweeteners,sweetener enhancers, pH modifiers, preservatives, and flavoring agents.

Suitable sweeteners include, but are not limited to, sucrose, aspartame,saccharin, dextrose, mannitol, xylitol, and combinations thereof.

If the formulations contain a sweetener, the formulations preferablycontain from about 0.001 to about 1% sweetener.

Suitable sweetness enhancers include, but are not limited to, theammonium salt forms of crude and refined Glycyrrhizic Acid. Magnasweet®products (available from Mafco Worldwide Corporation, Magnasweet is aregistered trademark of Mafco Worldwide Corporation) use the ammoniumsalt forms of crude and refined Glycyrrhizic Acid. Glycyrrhizic Acid isalso available as a pure derivative in the sodium and potassium saltforms.

If the formulations contain a sweetness enhancer, the formulationspreferably contain from about 0.001 to about 1% sweetness enhancer.

Suitable pH modifiers include, but are not limited to, hydrochloricacid, ascorbic acid, citric acid, sodium citrate, fumaric acid, sodiumhydroxide, sodium bicarbonate, sodium carbonate, ammonium carbonate, andcombinations thereof.

Suitable preservatives include, but are not limited to, methyl paraben,propyl paraben, benzyl alcohol, benzoic acid, sodium benzoate, sorbicacid, and combinations thereof.

Suitable flavoring agents include, but are not limited to, raspberry,peppermint oil, grape flavor, menthol, spearmint oil, citrus oil,cinnamon oil, strawberry flavor, cherry flavor, raspberry flavor, orangeoil, lemon oil, lemon mint flavor, fruit punch flavor, and combinationsthereof. In a preferred embodiment, the formulations contain fruit punchflavor, raspberry flavor, grape flavor, or lemon mint flavor.

If the formulations contain a flavoring agent, the formulationspreferably contain from about 0.001 to about 1% flavoring agent. In amore preferred embodiment, the formulations contain from about 0.005 toabout 0.5% of the flavoring agent.

The formulations are suitable for oral, buccal, sublingual, inhalationor intravenous/intramuscular administration. Preferably, theformulations are liquids administered orally.

Formulations Containing Lipids

In another embodiment, the invention is directed to stablepharmaceutical formulation for oral administration comprising from about0.1 to about 40% of a cannabinoid and from about 10 to about 95% of alipid.

In a preferred embodiment, the lipid is selected from the groupconsisting of sesame oil, olive oil, corn oil, sunflower oil, saffloweroil, flaxseed oil, almond oil, peanut oil, walnut oil, cashew oil,castor oil, coconut oil, palm oil, soybean oil, canola oil, vegetableoil, rice bran oil, medium chain glycerides, decanoyl glycerides,octanoyl glycerides, caprylic/capric triglycerides, oleoyl polyoxyl-6glycerides, linoleoyl polyoxyl-6 glycerides, polyglyceryl-3 dioleate,glyceryl monolinoleate, glyceryl monocaprylate, oleic acid, and acombination thereof. In a preferred embodiment, the lipid is selectedfrom the group consisting of sesame oil, sunflower oil, soybean oil,corn oil, a mixture of decanoyl glycerides and octanoyl glycerides, anda combination thereof.

Suitable commercial sources for the lipid include Miglyol 812Ncontaining a proprietary mixture of decanoyl and octanoyl glycerides(fatty acid esters) and Miglyol® 810N also containing a proprietarymixture of decanoyl and octanoyl fatty acids from coconut oil (Miglyolis available from and a registered trademark of Cremer Oleo GmbH & Co.).

In yet another embodiment, the formulations contain a cannabinoidselected from group consisting of cannabinol, cannabidiol, dronabinol(delta-9-tetrahydrocannabinol), delta-8-tetrahydrocannabinol,11-hydroxy-tetrahydrocannabinol,11-hydroxy-delta-9-tetrahydrocannabinol, levonantradol,delta-11-tetrahydrocannabinol, tetrahydrocannabivarin, amandamide,nabilone, acids, analogs, and synthetic derivatives thereof. In apreferred embodiment, the cannabinoid is cannabidiol.

In yet another embodiment, the formulations contain cannabidiol that issubstantially pure and synthetically synthesized which has a purity ofgreater than 98%. In a more preferred embodiment, the cannabidiol isgreater than 99% pure. In an even more preferred embodiment, thecannabidiol is greater than 99.5% pure. In a most preferred embodiment,the cannabidiol formulation contains less than 0.3%delta-9-tetrahydrocannabinol.

In a preferred embodiment, the formulations contain from about 1 toabout 35% of a cannabidiol. In a more preferred embodiment, theformulations contain from about 10 to about 32% cannabidiol. In a mostpreferred embodiment, the formulations contain from about 17 to about29% cannabidiol.

In a preferred embodiment, the formulations contain from about 20 toabout 90% of lipids. In a more preferred embodiment, the formulationscontain from about 50 to about 90% lipids. In a most preferredembodiment, the formulations contain from about 60 to about 85% lipids.

In yet another embodiment, the formulations contain alcohol. Theformulations can contain 0% alcohol. If the formulations containalcohol, they can include from about 0.1 to about 20% alcohol. In apreferred embodiment, the formulations contain from about 3 to about 17%alcohol. In a more preferred embodiment, the formulations contain fromabout 5 to about 15% alcohol.

In another embodiment, the formulations contain an antioxidant. Theformulations can contain 0% antioxidant. If the formulations containantioxidant, they can include from about 0.01 to about 1% of anantioxidant. In a preferred embodiment, the formulations contain fromabout 0.02 to about 0.5% antioxidant. In a more preferred embodiment,the formulations contain from about 0.03 to about 0.1% antioxidant.

Suitable antioxidants include butylated hydroxyltoluene, butylatedhydroxyl anisole, alpha-tocopherol (Vitamin E), ascorbyl palmitate,ascorbic acid, sodium ascorbate, ethylenediamino tetraacetic acid,cysteine hydrochloride, citric acid, sodium citrate, sodium bisulfate,sodium metabisulfite, lecithin, propyl gallate, sodium sulfate, andcombinations thereof. In a preferred embodiment, the formulationscontain alpha-tocopherol (Vitamin E), ascorbic acid, sodium ascorabte,ascobyl palminate or combinations thereof.

Suitable sweeteners include, but are not limited to, sucrose, aspartame,saccharin, dextrose, mannitol, xylitol, and combinations thereof.

If the formulations contain a sweetener, the formulations preferablycontain from about 0.1 to about 2% sweetener. In a more preferredembodiment, the formulations contain from about 0.1 to about 0.8%sweetener. In a most preferred embodiment, the formulations contain fromabout 0.2 to about 0.5% sweetener.

Suitable sweetness enhancers include, but are not limited to, theammonium salt forms of crude and refined Glycyrrhizic Acid. Magnasweet®products (available from Mafco Worldwide Corporation, Magnasweet is aregistered trademark of Mafco Worldwide Corporation) use the ammoniumsalt forms of crude and refined Glycyrrhizic Acid. Glycyrrhizic Acid isalso available as a pure derivative in the sodium and potassium saltforms.

If the formulations contain a sweetness enhancer, the formulationspreferably contain from about 0.001 to about 1% sweetness enhancer.

Suitable pH modifiers include, but are not limited to, hydrochloricacid, ascorbic acid, citric acid, sodium citrate, fumaric acid, sodiumhydroxide, sodium bicarbonate, sodium carbonate, ammonium carbonate, andcombinations thereof.

Suitable preservatives include, but are not limited to, methyl paraben,propyl paraben, benzyl alcohol, benzoic acid, sodium benzoate, sorbicacid, and combinations thereof.

Suitable flavoring agents include, but are not limited to, raspberry,peppermint oil, grape flavor, menthol, spearmint oil, citrus oil,cinnamon oil, strawberry flavor, cherry flavor, raspberry flavor, orangeoil, lemon oil, lemon mint flavor, fruit punch flavor, and combinationsthereof.

If the formulations contain a flavoring agent, the formulationspreferably contain from about 0.01 to about 1% flavoring agent. In amore preferred embodiment, the formulations contain from about 0.005 toabout 0.5% of the flavoring agent.

The formulations are suitable for oral, buccal, sublingual, inhalationor intravenous/intramuscular administration. Preferably, theformulations are liquids administered orally.

Exemplary Uses of Formulations of the Present Invention(Alcohol-Containing, Alcohol-Free, and Lipid) and SyntheticallySynthesized, Substantially Pure, Cannabidiol

The formulations of the present invention are especially suitable fortreatment of many diseases or disorders or symptoms of diseases anddisorders. Further, cannabidiol which is synthetically synthesized andsubstantially pure will be even more effective and suitable for thetreatment of diseases or symptoms of these diseases.

As first explained in U.S. Patent Application No. 62/004,495, Applicantunexpectedly created a new synthetic pathway for creating cannabidiol.This new process eliminated the need to grow Cannabis in order toextract cannabidiol. Applicant's cannabidiol has a high purity level andis substantially free of Schedule I drugs, includingdelta-9-tetrahydrocannabinol.

Applicant chemically synthesized cannadbidiol by combiningp-menthadienol and olivetol in toluene or dichloromethane or hexane witha p-toluene sulfonic acid catalyst to produce cannabidiol (see diagrambelow).

In an embodiment, the present invention is directed to methods fortreating a brain tumor comprising administering the formulations of thepresent invention to a patient in need thereof.

In another embodiment, the present invention is directed to methods fortreating a brain tumor comprising administering syntheticallysynthesized, substantially pure, cannabidiol to a patient in needthereof.

In an embodiment, the present invention is directed to methods fortreating glioma comprising administering the formulations of the presentinvention to a patient in need thereof.

In another embodiment, the present invention is directed to methods fortreating glioma comprising administering synthetically synthesized,substantially pure, cannabidiol to a patient in need thereof.

In an embodiment, the present invention is directed to methods fortreating glioblastoma multiforme comprising administering theformulations of the present invention to a patient in need thereof.

In another embodiment, the present invention is directed to methods fortreating glioblastoma multiforme comprising administering syntheticallysynthesized, substantially pure, cannabidiol to a patient in needthereof.

In an embodiment, the present invention is directed to methods fortreating Dravet Syndrome comprising administering the formulations ofthe present invention to a patient in need thereof.

In another embodiment, the present invention is directed to methods fortreating Dravet Syndrome comprising administering syntheticallysynthesized, substantially pure, cannabidiol to a patient in needthereof.

In yet another embodiment, the present invention is directed to methodsfor treating Lennox Gastaut Syndrome comprising administering theformulations of the present invention to a patient in need thereof.

In another embodiment, the present invention is directed to methods fortreating Lennox Gastaut Syndrome comprising administering syntheticallysynthesized, substantially pure, cannabidiol to a patient in needthereof.

In a further embodiment, the present invention is directed to methodsfor treating Mycolonic Seizures comprising administering theformulations of the present invention to a patient in need thereof. In amore preferred embodiment, the alcohol-free formulations containsubstantially pure cannabidiol.

In another embodiment, the present invention is directed to methods fortreating Mycolonic Seizures comprising administering syntheticallysynthesized, substantially pure, cannabidiol to a patient in needthereof.

In a further embodiment, the present invention is directed to methodsfor treating Juvenile Mycolonic Epilepsy comprising administering theformulations of the present invention to a patient in need thereof. In apreferred embodiment, the alcohol-free formulations of the presentinvention are administered to young patients in need of treatment.

In another embodiment, the present invention is directed to methods fortreating Juvenile Mycolonic Epilepsy comprising administeringsynthetically synthesized, substantially pure, cannabidiol to a patientin need thereof.

In an embodiment, the present invention is directed to methods fortreating Refractory Epilepsy comprising administering the formulationsof the present invention to a patient in need thereof. In a preferredembodiment, the alcohol-free formulations of the present invention areadministered to young patients in need of treatment.

In another embodiment, the present invention is directed to methods fortreating Refractory Epilepsy comprising administering syntheticallysynthesized, substantially pure, cannabidiol to a patient in needthereof.

In an embodiment, the present invention is directed to methods fortreating juvenile spasms comprising administering the formulations ofthe present invention to a patient in need thereof. In a preferredembodiment, the alcohol-free formulations of the present invention areadministered to young patients in need of treatment.

In another embodiment, the present invention is directed to methods fortreating juvenile spasms comprising administering syntheticallysynthesized, substantially pure, cannabidiol to a patient in needthereof.

In an embodiment, the present invention is directed to methods fortreating West Syndrome comprising administering the formulations of thepresent invention to a patient in need thereof. In a preferredembodiment, the alcohol-free formulations of the present invention areadministered to young patients in need of treatment.

In another embodiment, the present invention is directed to methods fortreating West Syndrome comprising administering syntheticallysynthesized, substantially pure, cannabidiol to a patient in needthereof.

In an embodiment, the present invention is directed to methods fortreating infantile spasms comprising administering the formulations ofthe present invention to a patient in need thereof. In a preferredembodiment, the alcohol-free formulations of the present invention areadministered to young patients in need of treatment.

In another embodiment, the present invention is directed to methods fortreating infantile spasms comprising administering syntheticallysynthesized, substantially pure, cannabidiol to a patient in needthereof.

In an embodiment, the present invention is directed to methods fortreating refractory infantile spasms comprising administering theformulations of the present invention to a patient in need thereof. In apreferred embodiment, the alcohol-free formulations of the presentinvention are administered to young patients in need of treatment.

In another embodiment, the present invention is directed to methods fortreating refractory infantile spasms comprising administeringsynthetically synthesized, substantially pure, cannabidiol to a patientin need thereof.

In an embodiment, the present invention is directed to methods fortreating tubular sclerosis complex comprising administering theformulations of the present invention to a patient in need thereof. In apreferred embodiment, the alcohol-free formulations of the presentinvention are administered to young patients in need of treatment.

In another embodiment, the present invention is directed to methods fortreating tubular sclerosis complex comprising administeringsynthetically synthesized, substantially pure, cannabidiol to a patientin need thereof.

In a further embodiment, the present invention is directed to methodsfor treating neuropathic pain comprising administering the formulationsof the present invention to a patient in need thereof. In a furtherembodiment, the neuropathic pain is caused by neurotoxic chemotherapyagents such as Paclitaxel, Docetaxel, Cisplatin, Oxaliplatin,Carboplatin, Vincristine, Methotrexate, Cytarabine, Fluorouracil,Ifosfamide, Cyclophosphamide, Procarbazine, etoposide, Carmustine, andLomustine. In yet another embodiment, the neuropathic pain is caused byPaclitaxel and the patient is receiving Paclitaxel due to a diagnosis ofbreast, cervical, endometrial and/or ovarian cancer. In a furtherembodiment, the breast, cervical, endometrial and/or ovarian cancer isplatinum-resistant. In another embodiment, the breast, cervical,endometrial and/or ovarian cancer is recurrent.

In another embodiment, the present invention is directed to methods fortreating neuropathic pain comprising administering syntheticallysynthesized, substantially pure, cannabidiol to a patient in needthereof. In a further embodiment, the neuropathic pain is caused byneurotoxic chemotherapy agents such as Paclitaxel, Docetaxel, Cisplatin,Oxaliplatin, Carboplatin, Vincristine, Methotrexate, Cytarabine,Fluorouracil, Ifosfamide, Cyclophosphamide, Procarbazine, etoposide,Carmustine, and Lomustine. In yet another embodiment, the neuropathicpain is caused by Paclitaxel and the patient is receiving Paclitaxel dueto a diagnosis of breast, cervical, endometrial and/or ovarian cancer.In a further embodiment, the breast, cervical, endometrial and/orovarian cancer is platinum-resistant. In another embodiment, the breast,cervical, endometrial and/or ovarian cancer is recurrent.

In a further embodiment, the present invention is directed to methodsfor using cannabidiol as an analgesic comprising administering theformulations of the present invention to a patient in need thereof.

In another embodiment, the present invention is directed to methods forusing cannabidiol as an analgesic comprising administering syntheticallysynthesized, substantially pure, cannabidiol to a patient in needthereof.

In a further embodiment, the present invention is directed to methodsfor treating opioid addiction withdrawal comprising administering theformulations of the present invention to a patient in need thereof. In apreferred embodiment, the alcohol-free formulations of the presentinvention are administered to the patient in need of treatment.

In another embodiment, the present invention is directed to methods fortreating opioid addiction withdrawal comprising administeringsynthetically synthesized, substantially pure, cannabidiol to a patientin need thereof.

In yet another embodiment, the present invention is directed to methodsfor treating cocaine addiction withdrawal comprising administering theformulations of the present invention to a patient in need thereof. In apreferred embodiment, the alcohol-free formulations of the presentinvention are administered to the patient in need of treatment.

In another embodiment, the present invention is directed to methods fortreating cocaine addiction withdrawal comprising administeringsynthetically synthesized, substantially pure, cannabidiol to a patientin need thereof.

In a further embodiment, the present invention is directed to methodsfor treating heroin addiction withdrawal comprising administering theformulations of the present invention to a patient in need thereof. In apreferred embodiment, the alcohol-free formulations of the presentinvention are administered to the patient in need of treatment.

In another embodiment, the present invention is directed to methods fortreating heroin addiction withdrawal comprising administeringsynthetically synthesized, substantially pure, cannabidiol to a patientin need thereof.

In a further embodiment, the present invention is directed to methodsfor treating nicotine addiction withdrawal comprising administering theformulations of the present invention to a patient in need thereof. In apreferred embodiment, the alcohol-free formulations of the presentinvention are administered to the patient in need of treatment.

In another embodiment, the present invention is directed to methods fortreating nicotine addiction withdrawal comprising administeringsynthetically synthesized, substantially pure, cannabidiol to a patientin need thereof.

In a further embodiment, the present invention is directed to methodsfor treating amphetamine addiction withdrawal comprising administeringthe formulations of the present invention to a patient in need thereof.In a preferred embodiment, the alcohol-free formulations of the presentinvention are administered to the patient in need of treatment.

In another embodiment, the present invention is directed to methods fortreating amphetamine addiction withdrawal comprising administeringsynthetically synthesized, substantially pure, cannabidiol to a patientin need thereof.

In an embodiment, the present invention is directed to methods fortreating acne comprising administering the formulations of the presentinvention to a patient in need thereof.

In another embodiment, the present invention is directed to methods fortreating acne comprising administering synthetically synthesized,substantially pure, cannabidiol to a patient in need thereof.

In an embodiment, the present invention is directed to methods fortreating Parkinson's disease comprising administering the formulationsof the present invention to a patient in need thereof.

In another embodiment, the present invention is directed to methods fortreating Parkinson's disease comprising administering syntheticallysynthesized, substantially pure, cannabidiol to a patient in needthereof.

In an embodiment, the present invention is directed to methods fortreating schizophrenia comprising administering the formulations of thepresent invention to a patient in need thereof.

In another embodiment, the present invention is directed to methods fortreating schizophrenia comprising administering syntheticallysynthesized, substantially pure, cannabidiol to a patient in needthereof.

In an embodiment, the present invention is directed to methods fortreating social anxiety disorder comprising administering theformulations of the present invention to a patient in need thereof.

In another embodiment, the present invention is directed to methods fortreating social anxiety disorder comprising administering syntheticallysynthesized, substantially pure, cannabidiol to a patient in needthereof.

In a further embodiment, the present invention is directed to methodsfor treating depression comprising administering the formulations of thepresent invention to a patient in need thereof.

In another embodiment, the present invention is directed to methods fortreating depression comprising administering synthetically synthesized,substantially pure, cannabidiol to a patient in need thereof.

In a further embodiment, the present invention is directed to methodsfor treating patients encountering adverse emotional stimuli comprisingadministering the formulations of the present invention to a patient inneed thereof.

In another embodiment, the present invention is directed to methods fortreating patients encountering adverse emotional stimuli comprisingadministering synthetically synthesized, substantially pure, cannabidiolto a patient in need thereof.

In an embodiment, the present invention is directed to methods fortreating nausea comprising administering the formulations of the presentinvention to a patient in need thereof.

In another embodiment, the present invention is directed to methods fortreating nausea comprising administering synthetically synthesized,substantially pure, cannabidiol to a patient in need thereof.

In an embodiment, the present invention is directed to methods fortreating multiple sclerosis comprising administering the formulations ofthe present invention to a patient in need thereof.

In another embodiment, the present invention is directed to methods fortreating multiple sclerosis comprising administering syntheticallysynthesized, substantially pure, cannabidiol to a patient in needthereof.

In an embodiment, the invention is directed to methods for treatingsymptoms of Cannabis use disorder comprising administering formulationsof the present invention to a patient in need thereof. In a preferredembodiment, the alcohol-free formulations of the present invention areadministered to the patient in need of treatment.

In another embodiment, the present invention is directed to methods fortreating symptoms of Cannabis use disorder comprising administeringsynthetically synthesized, substantially pure, cannabidiol to a patientin need thereof.

In another embodiment, the invention is directed to methods for treatingsymptoms of early psychosis comprising administering formulations of thepresent invention to a patient in need thereof.

In another embodiment, the present invention is directed to methods fortreating symptoms of early psychosis comprising administeringsynthetically synthesized, substantially pure, cannabidiol to a patientin need thereof.

In another embodiment, the invention is directed to methods for treatingsymptoms of Alzheimer's Disease comprising administering formulations ofthe present invention to a patient in need thereof.

In another embodiment, the present invention is directed to methods fortreating symptoms of Alzheimer's Disease comprising administeringsynthetically synthesized, substantially pure, cannabidiol to a patientin need thereof.

In yet another embodiment, the invention is directed to methods fortreating symptoms of post-traumatic stress disorder (“PTSD”) comprisingadministering formulations of the present invention to a patient in needthereof.

In another embodiment, the present invention is directed to methods fortreating symptoms of post-traumatic stress disorder PTSD comprisingadministering synthetically synthesized, substantially pure, cannabidiolto a patient in need thereof.

In an embodiment, the invention is directed to methods for treatingsymptoms of anxiety comprising administering formulations of the presentinvention to a patient in need thereof.

In another embodiment, the present invention is directed to methods fortreating anxiety comprising administering synthetically synthesized,substantially pure, cannabidiol to a patient in need thereof.

In a further embodiment, the invention is directed to methods fortreating symptoms of autism comprising administering formulations of thepresent invention to a patient in need thereof. In a preferredembodiment, the alcohol-free formulations of the present invention areadministered to the patient in need of treatment.

In another embodiment, the present invention is directed to methods fortreating symptoms of autism comprising administering syntheticallysynthesized, substantially pure, cannabidiol to a patient in needthereof.

Definitions

As used herein, a “patient” refers to a single patient and not a patientpopulation.

As used herein, “synthetic” refers to the chemical synthesis ofcannabidiol does not refer to cannabidiol that is extracted fromCannabis plant material.

As used herein, “substantially pure” refers to a preparation havingchromatographical purity of cannabidiol of greater than 98%, preferablygreater than 98.5%, more preferably greater than 99.0%, and mostpreferably greater than 99.5%.

As used herein, “substantially free of delta-9-tetrahydrocannabinol”refers to a preparation of cannabidiol having less than 0.3% ofdelta-9-tetrahydrocannabinol as determined by HPLC. Preferably, thepreparation contains less than 0.25% of delta-9-tetrahydrocannabinol,more preferably 0.2%, and most preferably less than 0.1% ofdelta-9-tetrahydrocannabinol.

As used herein, all numerical values relating to amounts, weights, andthe like, that are defined as “about” each particular value is plus orminus 10%. For example, the phrase “about 10% w/w” is to be understoodas “9% w/w to 11% w/w.” Therefore, amounts within 10% of the claimedvalue are encompassed by the scope of the claims.

As used here, “liquid” refers to a flowable, fluid pharmaceuticalformulation. This type of formulation is not a powder to solid.

All weights herein refer to % w/w or percent weight of the totalformulation.

As used herein the term “effective amount” refers to the amountnecessary to treat a patient in need thereof.

As used herein the term “pharmaceutically acceptable” refers toingredients that are not biologically or otherwise undesirable in anoral dosage form.

As used herein, “qs” means a sufficient quantity of that component toreach a desired volume or concentration.

The disclosed embodiments are simply exemplary embodiments of theinventive concepts disclosed herein and should not be considered aslimiting, unless the claims expressly state otherwise.

The following examples are intended to illustrate the present inventionand to teach one of ordinary skill in the art how to use theformulations of the invention. They are not intended to be limiting inany way.

All claims, aspects and embodiments of the invention, and specificexamples thereof, are intended to encompass equivalents thereof.

EXAMPLES Example 1. Alcohol-Free Formulations

The formulations in Table 1 below were prepared as follows. All thesolvents are purged with nitrogen before using in manufacturing. VitaminE, methyl paraben, propyl paraben were dissolved in propylene glycol.Polyethylene glycol 400 (PEG400) and a flavoring agent were added to thepropylene glycol solution and mixed thoroughly. The water phase wasprepared by dissolving sucralose and sodium ascorbate in water. Next,the solutions were combined and pH adjusted using a pH modifier. Thecannabinoid was added to the excipient solution and mixed untildissolved.

Synthetically synthesized, substantially pure, cannabidiol was used asthe cannabinoid.

Strawberry flavor was used as the flavoring agent.

TABLE 1 Alcohol-free Formulations Formulation # AF1 # AF2 # AF3 # AF4Cannabinoid 32 32 32 32 PEG400 28 28 27.9 28.4 Propylene Glycol 34 34 3434 Water 6 6 6 6 Vitamin E (Alpha- 0.05 Tocopherol) Sodium Ascorbate 0.10.1 Methyl Paraben 0.1 Propyl Paraben 0.02 Sucralose 0.05 Flavoring 0.3pH adjustment None pH pH pH adjusted adjusted adjusted to 6 to 7 to 6 to7 to 6 to 7 Final pH of 8.7 6.7 6.4 6.6 formulation

Example 2. Stability of Alcohol-Free Formulations

The formulations listed in Table 1 were subjected to stability at 55° C.2° C., 40° C.±2° C. under 75%±5% relative humidity, and 25° C.±2° C.under 60%±5% relative humidity. Stability of the formulations wasanalyzed at specified time points by evaluating for their potency (assayvalue) and impurity levels. Assay and impurities were detected usinghigh-performance liquid chromatography with an ultraviolet detector. Theassay was performed at 228 nm and indicated as a % of initialconcentration. For all impurities, analysis was performed at 228 nm andexpressed as a % area. Amounts of particular impurities are listed inTables 2 to 13 as a percentage of area of each formulation along withamount of total impurities. Relative retention time (RRT) is given foreach impurity.

TABLE 2 Stability Data for Cannabidiol Oral Solution Formulation # AF1stored at 55° C. ± 2° C. 0 1 2 3 4 55° C. - Formulation # AF1 RRT WeekWeek Weeks Weeks Weeks Assay (% of initial 100.00  97.11  97.30  94.47 87.91  concentration) % Cis-cannabidiol 1.440 0.01 0.02 0.02 0.02 0.02 %Delta-9-tetrahydrocannabinol 1.729 ND ND 0.01 ND 0.02 %Trans-(1R,6R)-3′-methyl- 1.840 0.05 0.03 0.03 0.03 0.02 cannabidiol %Unknown Impurity 0.328 ND BQL BQL BQL 0.06 0.345 ND BQL BQL BQL 0.070.385 ND BQL BQL BQL 0.05 0.404 ND 0.08 0.13 0.23 0.38 0.460 ND 0.050.07 0.10 0.17 0.486 ND 0.42 0.65 1.23 2.73 0.505 BQL 0.22 0.22 0.19 ND0.526 ND 0.10 0.14 0.13 0.17 0.610 ND ND BQL 0.05 0.08 0.702 ND BQL BQL0.07 0.08 0.742 ND BQL BQL 0.05 0.07 0.774 0.07 0.06 0.06 ND ND 0.796 ND0.58 1.04 2.13 3.80 0.830 BQL 0.31 0.39 0.59 0.87 0.933 ND BQL 0.06 0.170.37 1.881 ND 0.06 0.09 0.06 0.06 2.025 ND BQL BQL 0.34 0.39 2.291 ND0.06 ND ND ND Total Impurities (% Area) 0.13 1.99 2.91 5.39 9.41 ND—NotDetected BQL—Below Quantification Limit, for unknown impurity only

TABLE 3 Stability Data for Cannabidiol Oral Solution Formulation # AF2stored at 55° C. ± 2° C. 0 1 2 3 4 55° C. - Formulation # AF2 RRT WeekWeek Weeks Weeks Weeks Assay (% of initial 100.00  100.31  99.90  95.25 96.85  concentration) % Cis-cannabidiol 1.440 0.01 0.01 0.01 0.01 0.01 %Delta-9-tetrahydrocannabinol 1.730 ND ND 0.01 0.03 0.06 %Trans-(1R,6R)-3′-methyl- 1.840 0.05 0.07 0.05 0.05 0.04 cannabidiol %Unknown Impurity 0.340 ND BQL BQL 0.05 0.07 0.404 ND BQL BQL BQL 0.080.462 ND BQL BQL BQL 0.05 0.486 ND BQL 0.22 0.35 0.94 0.506 ND 0.07 0.130.15 ND 0.584 ND BQL BQL 0.05 0.11 0.776 0.07 0.07 0.06 0.05 ND 0.795 NDBQL 0.30 0.50 1.09 0.830 BQL BQL 0.10 0.14 0.22 0.932 ND BQL 0.07 0.100.18 2.034 ND ND BQL 0.09 BQL Total Impurities (% Area) 0.13 0.22 0.951.57 2.85 ND—Not Detected BQL—Below Quantification Limit, for unknownimpurity only

TABLE 4 Stability Data for Cannabidiol Oral Solution Formulation # AF3stored at 55° C. ± 2° C. 0 1 2 3 4 55° C. - Formulation # AF3 RRT WeekWeek Weeks Weeks Weeks Assay (% of initial 100.00  99.25  98.60  98.28 96.12 concentration) % Cis-cannabidiol 1.440 0.01 0.01 0.01 0.01 0.01 %Delta-9-tetrahydrocannabinol 1.736 ND ND ND 0.01 0.02 %Trans-(1R,6R)-3′-methyl- 1.840 0.05 0.05 0.05 0.05 0.05 cannabidiol %Unknown Impurity 0.484 ND ND ND BQL 0.14 0.502 ND BQL BQL 0.05 0.090.775 0.06 0.09 0.10 0.06 0.05 0.793 ND ND ND 0.06 0.27 0.830 BQL BQLBQL BQL 0.06 0.951 ND BQL ND BQL 0.05 1.158 ND 0.06 0.08 0.12 0.05 TotalImpurities (% Area) 0.12 0.21 0.24 0.36 0.79 ND—Not Detected BQL—BelowQuantification Limit, for unknown impurity only

TABLE 5 Stability Data for Cannabidiol Oral Solution Formulation # AF4stored at 55° C. ± 2° C. 0 1 2 3 4 55° C. - Formulation # AF4 RRT WeekWeek Weeks Weeks Weeks Assay (% of initial 100.00  100.92  99.27 100.16  98.10  concentration) % Cis-cannabidiol 1.440 0.01 0.01 0.010.01 0.01 % Trans-(1R,6R)-3′-methyl- 1.840 0.05 0.05 0.05 0.06 0.07cannabidiol % Unknown Impurity 0.403 ND BQL BQL BQL 0.06 0.485 ND BQL0.06 0.18 0.38 0.505 ND BQL 0.05 0.08 0.12 0.524 ND ND BQL BQL 0.070.776 0.07 0.08 0.05 0.06 ND 0.794 ND ND 0.07 0.31 0.70 0.822 ND ND BQL0.10 0.15 0.931 ND ND ND BQL 0.06 1.159 ND BQL 0.08 0.10 ND 1.774 ND NDND 0.05 0.11 Total Impurities (% Area) 0.13 0.14 0.37 0.95 1.73 ND—NotDetected BQL—Below Quantification Limit, for unknown impurity only

TABLE 6 Stability Data for Cannabidiol Oral Solution Formulation # AF1stored at 40° C. ± 2° C. under 75% ± 5% relative humidity 40°C.—Formulation # AF1 RRT 0 Week 2 Weeks 4 Weeks Assay (% of initialconcentration) 100.00 100.18 95.64 % Cis-cannabidiol 1.440 0.01% 0.01%0.01% % Trans-(1R, 6R)-3′-methyl- 1.846 0.05% 0.05% 0.03% cannabidiol %Unknown Impurity 0.404 ND BQL 0.12% 0.460 ND 0.07% 0.08% 0.486 ND 0.23%0.87% 0.505 BQL 0.30% 0.30% 0.526 ND 0.05% 0.14% 0.702 ND BQL 0.06%0.774 0.07% 0.07% ND 0.796 ND 0.25% 1.31% 0.830 BQL 0.12% 0.44% 0.931 NDND 0.06% Total Impurities (% Area) 0.13% 1.15% 3.42% ND—Not DetectedBQL—Below Quantification Limit, for unknown impurity only

TABLE 7 Stability Data for Cannabidiol Oral Solution Formulation # AF2stored at 40° C. ± 2° C. under 75% ± 5% relative humidity 40°C.—Formulation # AF2 RRT 0 Week 2 Weeks 4 Weeks Assay (% of initialconcentration) 100.00 100.08 98.77 % Cis-cannabidiol 1.442 0.01% 0.01%0.01% % Trans-(1R, 6R)-3′-methyl- 1.848 0.05% 0.05% 0.04% cannabidiol %Unknown Impurity 0.484 ND ND 0.08% 0.506 ND BQL 0.11% 0.776 0.07% 0.07%0.06% 0.794 ND ND 0.09% 0.830 BQL BQL 0.05% Total Impurities (% Area)0.13% 0.13% 0.44% ND—Not Detected BQL—Below Quantification Limit, forunknown impurity only

TABLE 8 Stability Data for Cannabidiol Oral Solution Formulation #AF3stored at 40° C. ± 2° C. under 75% ± 5% relative humidity 40°C.—Formulation # AF3 RRT 0 Week 2 Week 4 Week Assay (% of initialconcentration) 100.00 98.47 96.90 % Cis-cannabidiol 1.442 0.01% 0.01%0.01% % Trans-(1R, 6R)-3′-methyl- 1.846 0.05% 0.05% 0.05% cannabidiol %Unknown Impurity 0.775 0.06% 0.08% 0.10% 1.160 ND ND 0.05% TotalImpurities (% Area) 0.12% 0.14% 0.21% ND—Not Detected

TABLE 9 Stability Data for Cannabidiol Oral Solution Formulation # AF4stored at 40° C. ± 2° C. under 75% ± 5% relative humidity 40°C.—Formulation # AF4 RRT 0 Week 2 Weeks 4 Weeks Assay (% of initialconcentration) 100.00 99.63 99.50 % Cis-cannabidiol 1.437 0.01% 0.01%0.01% % Trans-(1R, 6R)-3′-methyl- 1.840 0.05% 0.05% 0.06% cannabidiol %Unknown Impurity 0.776 0.07% 0.07% 0.08% Total Impurities (% Area) 0.13%0.13% 0.15%

TABLE 10 Stability Data for Cannabidiol Oral Solution Formulation # AF1stored at 25° C. ± 2° C. under 60% ± 5% relative humidity 25°C.—Formulation # AF1 RRT 0 Week 4 Weeks Assay (% of initialconcentration) 100.00 101.24 % Cis-cannabidiol 1.440 0.01% 0.01% %Trans-(1R, 6R)-3′-methyl- 1.846 0.05% 0.04% cannabidiol % UnknownImpurity 0.459 ND 0.09% 0.483 ND 0.11% 0.505 BQL 0.27% 0.774 0.07% 0.06%0.796 ND 0.10% 0.836 BQL 0.06% Total Impurities (% Area) 0.13% 0.74%ND—Not Detected BQL—Below Quantification Limit, for unknown impurityonly

TABLE 11 Stability Data for Cannabidiol Oral Solution Formulation # AF2stored at 25° C. ± 2° C. under 60% ± 5% relative humidity 25°C.—Formulation # AF2 RRT 0 Week 4 Weeks Assay (% of initialconcentration) 100.00 100.22 % Cis-cannabidiol 1.442 0.01% 0.01% %Trans-(1R, 6R)-3′-methyl- 1.848 0.05% 0.05% cannabidiol % UnknownImpurity 0.776 0.07% 0.07% Total Impurities (% Area) 0.13% 0.13%

TABLE 12 Stability Data for Cannabidiol Oral Solution Formulation # AF3stored at 25° C. ± 2° C. under 60% ± 5% relative humidity 25°C.—Formulation # AF3 RRT 0 Week 4 Weeks Assay (% of initialconcentration) 100.00 97.52 % Cis-cannabidiol 1.442 0.01% 0.01% %Trans-(1R, 6R)-3′-methyl- 1.846 0.05% 0.05% cannabidiol % UnknownImpurity 0.775 0.06% 0.08% Total Impurities (% Area) 0.12% 0.14%

TABLE 13 Stability Data for Cannabidiol Oral Solution Formulation # AF4stored at 25° C. ± 2° C. under 60% ± 5% relative humidity 25°C.—Formulation # AF4 RRT T = 0 4 Weeks Assay (% of initialconcentration) 100.00 99.26 % Cis-cannabidiol 1.437 0.01% 0.01% %Trans-(1R, 6R)-3′-methyl- 1.840 0.05% 0.06% cannabidiol % UnknownImpurity 0.776 0.07% 0.07% Total Impurities (% Area) 0.13% 0.14%

Control formulation (#AF1) showed significant increase in levels oftotal impurities and decrease in the assay value. Adjusting the pH offormulation (#AF2) in the range of from about 6 to about 7 increased thestability of the formulation in comparison to control formulation. Thisillustrates the critical role that pH plays in cannabinoid formulations'stability. Applicant determined that the pH should be from about 6 toabout 7 for optimal stability. Addition of antioxidants along with pHadjustment further increased the stability of the cannabinoidformulation. For example, formulations #AF3 and #AF4, containingantioxidant(s) and pH modifiers, showed excellent stability for fourweeks regardless of temperature and humidity conditions.

Example 3. Alcohol Formulations

The formulations in Tables 14 and 15 below were prepared as follows. Allthe solvents were purged with nitrogen before using in manufacturing.Vitamin E, ascorbyl palmitate, methyl paraben, propyl paraben, sucralosewere dissolved in ethanol. propylene glycol, polyethylene glycol 400,glycerol, flavoring agent, and water were added to the solution andmixed thoroughly. Then, if applicable, the pH of the solution wasadjusted using a pH modifier. The cannabinoid was added to the excipientsolution and mixed until completely dissolved.

Synthetically synthesized, substantially pure, cannabidiol was used asthe cannabinoid. Strawberry flavor was used as the flavoring agent.

TABLE 14 Formulations with Alcohol Formulation # A5 # A6 # A7 # A8Cannabinoid 9.1 9.1 9.1 8.8 Polyethylene glycol 400 3 3 3 3 PropyleneGlycol 7.5 7.5 7.5 7.5 Ethanol 50.3 50.2 50.2 49.7 Water 30 30 30 30.5Vitamin E (Alpha-Tocopherol) 0.05 0.05 0.05 Ascorbyl Palmitate 0.1 0.10.1 Sucralose 0.05 0.05 0.05 0.05 Methyl Paraben 0.02 0.02 0.02 0.02Propyl Paraben 0.02 0.02 0.02 0.02 Flavoring 0.3 pH adjustment None NonepH pH adjusted adjusted to 6 to 7 to 6 to 7 Final pH of formulation 6.064.9 6.5 6.4

TABLE 15 Formulations Additional with Alcohol Formulation #A9 #A10Cannabinoid 32 32 Polyethylene glycol 400 18.8 23.8 Propylene Glycol 3939 Glycerol 5 Ethanol 5 5 Vitamin E (Alpha Tocopherol) 0.05 0.05Ascorbyl Palmitate 0.1 0.1 Sucralose 0.05 0.05 Methyl Paraben 0.02 0.02Propyl Paraben 0.02 0.02

Example 4. Stability of Formulations with Alcohol

The formulations listed in Table 14 and Table 15 were subjected tostability at 25° C.±2° C. under 60%±5% relative humidity and 40° C.±2°C. under 75%±5% relative humidity. Stability of the formulations wasanalyzed at specified time points by evaluating for their potency (assayvalue) and impurity levels. Assay and impurities were detected usinghigh-performance liquid chromatography with an ultraviolet detector. Theassay was performed at 228 nm and indicated as a % of initialconcentration. For all impurities, analysis was performed at 228 nm andexpressed as a % area. Amounts of particular impurities are listed inTable 16 to 22 as a percentage of area of each formulation along withamount of total impurities. Relative retention time (RRT) is given foreach impurity.

TABLE 16 Stability Data for Cannabidiol Oral Solution Formulation # A5stored at 25° C. ± 2° C. under 60% ± 5% relative humidity 25° C. -Formulation # A5 RRT 0 Month 3 Months 6 Months 9 Months 12 Months Assay(% of initial 100.00  92.97  83.87  77.31  68.92  concentration) %Cannabinol 1.400 ND ND ND 0.01 ND % Cis-cannabidiol 1.455 0.01 0.01 0.010.02 0.02 % Delta-9- 1.761 ND ND 0.01 0.15 0.17 tetrahydrocannabinol %Unknown Impurity 0.319 ND 0.08 0.18 0.34 0.39 0.337 ND BQL BQL BQL 0.050.370 ND BQL 0.07 0.08 0.08 0.389 ND 0.11 0.24 0.42 0.54 0.448 ND 0.180.23 0.24 0.25 0.479 ND 0.78 1.65 2.66 3.49 0.494 ND 0.50 0.72 0.82 0.880.522 ND 0.05 BQL BQL BQL 0.600 ND BQL 0.05 0.09 0.15 0.678 ND BQL 0.100.16 0.21 0.697 ND BQL 0.08 0.08 0.09 0.713 ND ND ND 0.06 0.10 0.7700.05 ND ND ND ND 0.790 ND 0.99 2.28 4.19 5.55 0.819 ND 0.39 0.87 1.441.97 0.930 ND 0.05 0.21 0.38 0.56 1.189 ND ND ND BQL 0.09 2.053 ND 0.07ND BQL 0.14 3.192 ND ND ND ND 0.09 3.256 ND ND ND 0.08 0.08 3.650 ND NDND ND 0.13 Total Impurities (% Area) 0.06 3.21 6.70 11.22  15.03  ND—NotDetected BQL—Below Quantification Limit, for unknown impurity only

TABLE 17 Stability Data for Cannabidiol Oral Solution Formulation # A6stored at 25° C. ± 2° C. under 60% ± 5% relative humidity 25° C. -Formulation # A6 RRT 0 Month 3 Months 6 Months 9 Months 12 Months Assay(% of initial 100.00  97.49  94.25  91.14  87.53  concentration) %Cannabinol 1.400 ND ND ND 0.01 ND % Cis-cannabidiol 1.455 0.01 0.01 0.010.01 ND % Delta-9- 1.761 ND 0.06 0.23 0.68 0.82 tetrahydrocannabinol %Unknown Impurity 0.390 ND BQL 0.05 0.10 0.14 0.479 ND BQL 0.08 0.17 0.250.496 ND 0.20 0.87 1.80 2.41 0.577 ND BQL BQL 0.08 0.10 0.721 ND ND BQLBQL 0.05 0.770 0.05 0.05 BQL BQL BQL 0.790 ND 0.05 0.11 0.25 0.43 0.834BQL BQL BQL 0.05 0.07 0.961 ND 0.06 0.33 0.71 0.97 1.197 ND ND ND ND0.06 1.869 BQL BQL BQL 0.06 0.27 2.066 ND 0.07 0.42 0.59 0.86 3.247 NDND ND 0.07 0.08 3.655 ND ND ND ND 0.11 Total Impurities (% Area) 0.060.50 2.10 4.58 6.62 ND—Not Detected BQL—Below Quantification Limit, forunknown impurity only

TABLE 18 Stability Data for Cannabidiol Oral Solution Formulation # A7stored at 25° C. ± 2° C. under 60% ± 5% relative humidity 25° C. -Formulation # A7 RRT 0 Month 3 Months 6 Months 9 Months 12 Months Assay(% of initial 100.00  98.69  96.52  96.30  96.54  concentration) %Cis-cannabidiol 1.455 0.01 0.01 0.01 0.01 0.01 % Delta-9- 1.761 ND 0.010.02 0.03 0.05 tetrahydrocannabinol % Unknown Impurity 0.479 ND BQL BQLBQL 0.07 0.495 ND BQL 0.06 0.14 0.20 0.770 0.05 0.05 0.05 0.05 BQL 0.793ND BQL 0.06 0.06 0.10 0.958 ND ND ND BQL 0.06 1.160 ND BQL 0.05 BQL 0.051.883 ND ND ND ND 0.06 2.057 ND ND BQL BQL 0.06 3.652 ND ND ND ND 0.05Total Impurities (% Area) 0.06 0.07 0.25 0.29 0.71 ND—Not DetectedBQL—Below Quantification Limit, for unknown impurity only

TABLE 19 Stability Data for Cannabidiol Oral Solution Formulation #A8stored at 25° C. ± 2° C. under 60% ± 5% relative humidity 25°C.-Formulation #A8 RRT 0 Month 3 Months 6 Months Assay (% of initial100.00 100.51 100.14 concentration) % Cis-cannabidiol 1.454 0.04 0.040.04 % Delta-9- 1.762 0.03 0.04 0.05 tetrahydrocannabinol % UnknownImpurity 0.501 BQL BQL 0.07 1.162 ND BQL 0.07 1.198 ND ND 0.05 TotalImpurities (% Area) 0.07 0.08 0.28 ND-Not Detected BQL-BelowQuantification Limit, for unknown impurity only

TABLE 20 Stability Data for Cannabidiol Oral Solution Formulation #A7stored at 40° C. ± 2° C. under 75% ± 5% relative humidity 40°C.-Formulation #A7 RRT 0 Month 3 Months 6 Months Assay (% of initial100.00 95.22 89.72 concentration) % Cis-cannabidiol 1.451 0.01 0.01 0.01% Delta-9- 1.753 0.01 0.06 0.16 tetrahydrocannabinol % Unknown Impurity0.390 ND 0.05 0.15 0.450 ND BQL 0.06 0.476 BQL 0.23 0.75 0.501 BQL 0.300.80 0.609 ND BQL 0.05 0.675 ND BQL 0.05 0.772 0.05 BQL ND 0.791 ND 0.361.35 0.830 BQL 0.12 0.37 0.934 ND BQL 0.25 0.958 ND BQL 0.18 1.333 ND ND0.05 1.982 ND ND 0.17 2.062 BQL 0.05 0.32 3.253 ND BQL 0.09 3.744 ND ND0.13 Total Impurities 0.07 1.18 4.94 (% Area) ND-Not Detected BQL-BelowQuantification Limit, for unknown impurity only

TABLE 21 Stability Data for Cannabidiol Oral Solution Formulation #A8stored at 40° C. ± 2° C. under 75% ± 5% relative humidity 40° C.- 0 3 6Formulation #A8 RRT Month Months Months Assay (% of initial 100.00 96.5792.84 concentration) % Cis-cannabidiol 1.454 0.04 0.03 0.03 % Delta-9-1.762 0.03 0.13 0.62 tetrahydrocannabinol % 0.392 ND 0.06 0.14 Unknown0.478 ND 0.22 0.64 Impurity 0.501 BQL 0.41 0.84 0.610 ND BQL 0.05 0.670ND BQL 0.05 0.792 ND 0.38 1.15 0.821 ND 0.12 0.30 0.931 ND 0.05 0.190.956 ND 0.09 0.21 2.068 BQL 0.11 0.23 3.251 ND BQL 0.09 3.754 ND ND0.13 Total Impurities (% Area) 0.07 1.60 4.67 ND-Not Detected BQL-BelowQuantification Limit, for unknown impurity only

TABLE 22 Stability Data for Cannabidiol Oral Solution Formulation #A9stored at 40° C. ± 2° C. under 75% ± 5% relative humidity 0 2 4 40°C.-Formulation #A9 RRT Week Weeks Weeks Assay (% of initial 100.00 99.77100.65 concentration) % Cis-cannabidiol 1.440 0.01 0.01 0.01 %Trans-(1R, 6R)-3’- 1.841 0.05 0.06 0.05 methyl-cannabidiol % UnknownImpurity 0.770 0.06 0.07 0.08 Total Impurities (% Area) 0.12 0.14 0.14

TABLE 23 Stability Data for Cannabidiol Oral Solution Formulation #A10stored at 40° C. ± 2° C. under 75% ± 5% relative humidity 40° C.- 0 2 4Formulation #A10 RRT Week Weeks Weeks Assay (% of initial 100.00 101.25100.78 concentration) % Cis-cannabidiol 1.440 0.01 0.01 0.01 % Delta-9-1.723 ND ND 0.01 tetrahydrocannabinol % Trans-(1R, 6R)-3’- 1.842 0.050.05 0.05 methyl-cannabidiol % Unknown Impurity 0.770 0.07 0.07 0.06Total Impurities (% Area) 0.13 0.13 0.13 ND-Not Detected

Control formulation (#A5) showed significant increase in levels of totalimpurities and decrease in the assay value. The addition ofantioxidants, Vitamin E and ascorbyl palmitate (see #A6) significantlyincreased the stability of formulation. These results illustrate thecritical role of antioxidants in stabilizing cannabinoid formulations.Antioxidants Vitamin E and ascorbic acid (or its salt) show excellentsynergism as ascorbic acid (or its salt) strongly inhibits the depletionof Vitamin E by regenerating it. Along with the antioxidants, theaddition of pH modifiers to adjust the pH to the range of 6 to 7resulted in exceptionally stable formulations (#A7 and #A8). Thestability testing data illustrates that the pH range of from about 6 toabout 7 is critical. Formulations #A9 and #A10 also showed goodstability after four weeks.

Example 5: Lipid Formulations

The formulations in Table 24 were created by mixing all the solid andliquid excipients in the lipid. Cannabidiol was then dissolved.Synthetically synthesized, substantially pure, cannabidiol used as thesource of the cannabinoid. Strawberry was used as the source offlavoring.

TABLE 24 Formulations with Lipids Formulation # LF1 # LF2 # LF3 # LF4 #LF5 # LF6 # LF7 Cannabinoid 24.60 19.50 19.50 19.50 19.50 18.00 28.00Vitamin E (Alpha 0.05 0.05 0.05 0.05 0.05 0.05 Tocopherol) Flavor 0.300.30 0.30 0.30 0.30 Sesame oil 75.40 80.15 70.15 Sunflower oil 80.45Soybean oil 81.95 Corn Oil 80.45 A mixture of decanoyl and 61.95octanoyl glycerides (fatty acid esters) Ethanol 10.00 10.00

Example 6: Stability of a Formulation with Lipids

Formulation #LF1 was subjected to stability at 25° C.±2° C. under 60% 5%relative humidity and 40° C.±2° C. under 75%±5% relative humidity. Thestability of the formulation was analyzed at specified time points byevaluating the potency (assay value) and impurity levels. Assay andimpurities were detected using high-performance liquid chromatographywith an ultraviolet detector. The assay was performed at 228 nm andindicated as a % of initial concentration. For all impurities, analysiswas performed at 228 nm and expressed as a % area. Amounts of particularimpurities are listed in Table 25 as a percentage of area of eachformulation along with amount of total impurities. Relative retentiontime (RRT) is given for each impurity.

TABLE 25 Three Month Stability Data for Cannabidiol Oral SolutionFormulation #LF1 stored at 40° C. ± 2° C. under 75% ± 5% relativehumidity and stored at 25° C. ± 2° C. under 60% ± 5% relative humidity 33 0 Months- Months- Formulation #LF1 RRT Month 40° C. 25° C. Assay (% ofinitial 100.00 100.87 100.72 concentration) % Cis-cannabidiol 1.437 0.030.04 0.04 % Delta 9-THC 1.736 0.06 0.06 0.08 % Trans-(1R, 6R)-3’- 1.8400.02 0.06 0.02 methyl-cannabidiol Total Impurities (% Area) 0.11 0.160.14

As seen in Table 25 above, formulation #LF1 with sesame oil showed goodstability after 3 months at both storage conditions 25° C.±2° C./60%±5%relative humidity and 40° C.±2° C./75%±5% relative humidity.

Example 7. Paclitaxel Induced Neuropathic Pain Study

Paclitaxel is an antineoplastic agent that has activity against severaltypes of cancer including ovary, breast, lung and the head and neck.Paclitaxel works by promoting microtubule assembly which results inneuropathy as a toxic side effect. Peripheral sensory neuropathy is themost commonly reported neurotoxic side effect of paclitaxel and itlimits treatment with high and cumulative doses of paclitaxel when givenalone or in combination with other neurotoxic antineoplastic agents suchas cisplatin. Currently there is not a highly effective treatment forthis type of pain. Therefore, there is a need for a highly effectivetreatment to relieve the symptoms of paclitaxel induced neuropathy.

A mouse study was conducted in order to determine the effects ofcannabidiol, delta-9-tetrahydrocannabinol, and cannabidiol plusdelta-9-tetrahydrocannabinol combinations to alleviate neuropathic paincaused by chemotherapy-induced peripheral neuropathy. The cannadidioladministered to the mice was substantially pure, syntheticallysynthesized, cannabidiol which had a purity greater than 98%.

A detailed explanation of FIG. 1 is as follows. The Y-axes represent thethreshold sensitivity to mechanical stimulation, expressed as a percentof baseline sensitivity. The X-axes represent the dose of drug mg/kgadministered intraperitoneally. Whereas the dotted lines representwithdrawal threshold level to mechanical stimulation of saline controls,the dashed lines represent paclitaxel-treated animals. The points alongthe dashed line indicate neuropathic pain while points along the dottedline represent protection from neuropathic pain. The data shown aremean+SEM sensitivity measured on Day 21 post treatment. * p<0.05 fromsaline control as determined by one-way ANOVA.

Specific doses of agents producing similar overt behavioral effects whenadded to together should produce the additive effect level.

Examples

-   -   1) If 1.25 mg/kg cannabidiol produces 100% alleviation of pain        effect and 1.25 mg/kg delta-9-tetrahydrocannabinol produces 0%        effect, then those doses added together should be fully        effective (as should the 2.5 mg/kg cannabidiol+2.5 mg/kg        delta-9-tetrahydrocannabinol).    -   2) If 0.625 mg/kg cannabidiol and 0.625        delta-9-tetrahydrocannabinol produce 0% effect, then those doses        in combination should be ineffective.

Applicant found (as illustrated in FIG. 1) that cannabidiol whenadministered alone provided the most effective level of alleviatingchemotherapy-induced neuropathic pain compared todelta-9-tetrahydrocannabinol. The presence ofdelta-9-tetrahydrocannabinol depending on its concentration can inhibitthe ability of cannabidiol to alleviate neuropathic pain. The ability ofdelta-9-tetrahydrocannabinol to block the pain alleviating activity ofcannabidiol is also dependent of the concentration of cannabidiol. Thistest illustrates that a substantially pure cannabidiol formulation ishighly desirable.

Example 8. Anticonvulsant Study

This study was conducted as follows according to standard models foranticonvulsant screening including the maximal electroshock test(“IVIES”), the minimal clonic seizure (“6 Hz”) test and evaluations oftoxicity (“TOX”). The data was recorded as number of animals protected(N) out of the number of animals tested (F), see Tables 26 to 29 below.The test was repeated one time. The cannabidiol administered to the miceand rats was substantially pure, synthetically synthesized, cannabidiolwhich had a purity greater than 98%. The cannabidiol was dissolved in0.5% methylcellulose or a 1:1:18 ratio of ethanol:polyethoxylated castoroil:phosphate buffered saline (“PBS”).

The maximal electroshock test is a model for generalized tonic-clonicseizures and provides an indication of a compound's ability to preventseizure spread when all neuronal circuits in the brain are maximallyactive. These seizures are highly reproducible and areelectrophysiologically consistent with human seizures. For all testsbased on maximal electroshock convulsions, 60 Hz of alternating current(50 mA in mice, 150 in rats) was delivered for 0.2 s by cornealelectrodes which were primed with an electrolyte solution containing ananesthetic agent (0.5% tetracaine HCl). The mice were tested at variousintervals following doses of 10, 30 and 100 mg/kg of cannabidiol givenby intraperitoneal injection of a volume of 0.01 mL/g. An animal wasconsidered “protected” from maximal electroshock-induced seizures uponabolition of the hindlimb tonic extensor component of the seizure.

The minimal motor impairment test was used to determine the compounds'undesirable side effects or toxicity. During this test, the animals weremonitored for overt signs of impaired neurological or muscular function.The rotorod procedure was used to disclose minimal muscular orneurological impairment. When a control mouse is placed on a rod thatrotates at a speed of 6 rpm, the animal can maintain its equilibrium forlong periods of time. The animal was considered toxic if it fell offthis rotating rod three times during a 60 second period. In addition tominimal motor impairment, the animals may have exhibited a circular orzigzag gait, abnormal body posture and spread of the legs, tremors,hyperactivity, lack of exploratory behavior, somnolence, stupor,catalepsy, loss of placing response and changes in muscle tone.

The third test was the minimal clonic seizure (6 Hz) test. Like themaximal electroshock test, the minimal clonic seizure (6 Hz) test isused to assess a compound's efficacy against electrically inducedseizures but uses a lower frequency (6 Hz) and longer duration ofstimulation (3 s). Cannabidiol was pre-administered to mice viaintraperitoneal injection. At varying times, individual mice (four pertime point) were challenged with sufficient current delivered throughcorneal electrodes to elicit a psychomotor seizure in 97% of animals (32mA for 3 s). Untreated mice will display seizures characterized by aminimal clonic phase followed by stereotyped, automatistic behaviorsdescribed originally as being similar to the aura of human patients withpartial seizures. Animals not displaying this behavior are consideredprotected.

TABLE 26 Anticonvulsant Screening, Mice, Methylcellulose Time (Hours)0.5 1.0 2.0 Test Dose N/F N/F N/F 6HZ 10 0/4 0/4 0/4 6HZ 30 0/4 0/4 0/46HZ 100 1/4 0/4 0/4 MES 10 0/4 0/4 0/4 MES 30 0/4 0/4 0/4 MES 100 0/41/4 2/4 TOX 10 0/8 0/8 0/8 TOX 30 0/8 0/8 0/8 TOX 100 0/8 0/8 0/8

TABLE 27 Anticonvulsant Screening, Mice, Ethanol:Polyethoxylated castoroil:PBS Time (Hours) 0.5 1.0 2.0 Test Dose N/F N/F N/F 6HZ 10 0/4 0/40/4 6HZ 30 0/4 0/4 0/4 6HZ 100 2/4 0/4 0/4 MES 10 0/4 0/4 0/4 MES 30 0/41/4 0/4 MES 100 0/4 2/4 1/4 TOX 10 0/8 0/8 0/8 TOX 30 0/8 0/8 0/8 TOX100 0/8 0/8 0/8

TABLE 28 Anticonvulsant Screening, Rats, Methylcellulose Time (Hours)1.0 2.0 4.0 Test Dose N/F N/F N/F MES 30 0/4 0/4 0/4 MES 100 0/4 0/4 0/4TOX 30 0/4 0/4 0/4 TOX 100 0/4 0/4 0/4

TABLE 29 Anticonvulsant Screening, Rats, Ethanol:Polyethoxylated castoroil:PBS Time (Hours) 1.0 2.0 4.0 Test Dose N/F N/F N/F MES 30 0/4 0/40/4 MES 100 1/4 0/4 0/4 TOX 30 0/4 0/4 0/4 TOX 100 0/4 0/4 0/4

As seen in Tables 26 to 29 above, Applicant found that cannabidiolprotected the mice and rats from epilepsy.

Example 9. Glioblastoma Multiforme Study

A study was conducted in order to determine the extent to which systemicadministration of cannabidiol or cannabidiol plusdelta-9-tetrahydrocannabinol (cannabidiol/delta-9-tetrahydrocannabinol1:1) can inhibit glioblastoma multiforme progression and enhance theactivity of temozolomide, a chemotherapy drug, in an orthotopic mousemodel of glioblastoma multiforme utilizing U87 cells. It was previouslysuggested that the combination of cannabidiol plusdelta-9-tetrahydrocannabinol is the most effective treatment fortargeting tumors derived from U87 serum-derived glioblastoma multiformecells.

The study was conducted as follows. Human U87 luciferase labeled cellswere grown in Roswell Park Memorial Institute media with 10% fetalbovine serum and then harvested from dishes while in their exponentialgrowth phase in culture with 0.1% trypsin/ethylenediaminetetraaceticacid and washed twice with serum-free Roswell Park Memorial Institutemedia. For the intracranial model, tumors were generated in femaleathymic nu/nu mice by the intracranial injection of 0.3×10⁶ U87 cells in4 μl of Roswell Park Memorial Institute media. Using this model, you canassess drug efficacy (in vivo imaging) as well as survival in the samegroup of animals. Survival studies were carried out in accordance withthe National Institutes of Health's guidelines involving experimentalneoplasia and our approved Institutional Animal Care and Use Committeesprotocol. Animals in all groups are removed from the study when theydemonstrate any single sign indicative of significant tumor burdendevelopment, including hunched back, sustained decreased generalactivity, or a significant decrease in weight. In limited cases wheretumors were able to escape the intracranial space, the mice wereeuthanized when the external tumors measured greater than 5 mm asassessed by callipers. Additionally, mice with tumors measuring >500×10⁶radiance where removed from the study even if symptoms were not observedto assure spontaneous deaths related to seizures did not occur do to theexistence of the large intracranial tumor.

The cannabinoids were dissolved in a mixture of 3% ethanol, 3%surfactant and 94% saline, and temozolomide was dissolved in 30%dimethyl sulfoxide and 70% saline. Cannabidiol that was syntheticallysynthesized and substantially pure was used in this study. Thetreatments were initiated 9 days after the injection of the tumor cells.Mice were imaged the morning before the first injection to determineinitial tumor size and then groups were organized to have equaldistribution of tumor size before the initiation of the first injection.Mice were treated once a day for five days with temozolomide. Mice weretreated once a day, 5 days a week (Monday through Friday), with thecannabinoids until the completion of the study, except for the firstweek of the study where mice were injected over the weekend. All micewere administered the treatments via intraperitoneal injection. Therewere 12 mice per group, for a total of 72 mice. The treatment rates wereas follows: cannabidiol (15 mg/kg);cannabidiol/delta-9-tetrahydrocannabinol (1:1, together @ 15 mg/kg); andtemozolomide (2 mg/kg intraperitoneal injection.

Significant differences were determined using a one-way ANOVA.Bonferroni-Dunn post-hoc analyses were conducted when appropriate.Survival between groups was compared using a long-rank Mantel-Cox test.P values <0.05 defined statistical significance.

A detailed explanation of FIG. 2 is as follows. The X-axis representsthe number of days after treatment and the Y-axis represents thesurvival rates.

As seen in FIG. 2, while 15 mg/kg of cannabidiol alone orcannabidiol/delta-9-tetrahydrocannabinol (1:1) did not inhibitglioblastoma multiforme progression, it enhanced the antitumor activityof suboptimal doses of temozolomide leading to a significant increase insurvival. Further, the substantially pure, synthetically synthesized,cannabidiol produced full regression of 20% of tumors. This effect wasnot observed following the 1:1 cannabidiol:delta-9-tetrahydrocannabinoltreatments. It was unexpected that substantially pure, syntheticallysynthesized, cannabidiol would have these effects because previously itwas thought that a 1:1 ratio of cannabidiol (that was extracted fromCannabis and not substantially pure):delta-9-tetrahydrocannabinol wouldproduce better effects than cannabidiol alone. However, this study againillustrates the superiority of Applicant's substantially pure,synthetically synthesized, cannabidiol.

Example 10. 6 Hz Psychomotor Seizure Test

This study was conducted in order to determine the ability ofsynthetically-synthesized, substantially pure cannabidiol to block apsychomotor seizure induced by long-duration frequency (6 Hz)stimulation. This is a study model for therapy-resistant partialseizures.

Adult male CF1 mice (weighing 18 to 25 g) were pretreatedintraperitoneally with the cannabidiol at a dose of 100 mg/kg. Thecannabidiol administered to the mice was substantially pure,synthetically synthesized, cannabidiol which had a purity greater than98%. The cannabidiol was dissolved in 0.5% methylcellulose or a 1:1:18ratio of ethanol:polyethoxylated castor oil:PBS.

Each treatment group (n=4 mice/group) was examined for anticonvulsiveeffects at one of five time points (1/4, 1/2, 1, 2, and 4 hours)following treatment with cannabidiol. Following pretreatment, each mousereceived a drop of 0.5% tetracaine hydrochloride applied to each eye.The mouse was then challenged with the low-frequency (6 Hz) stimulationfor 3 seconds delivered through corneal electrodes. The low-frequency,long-duration stimuli was initially delivered at 32 mA intensity.Animals were manually restrained and released immediately following thestimulations and observed for seizure activity. If the test compound waseffective in the 32 mA screen, an additional assay wherein thestimulation current is increased to 44 mA is employed using the sameprotocol as described above. Additionally, a dose response curve can begenerated at the time of peak effect (TPE) at the specific stimulationintensity.

Typically, the 6 Hz stimulation results in a seizure characterized by aminimal clonic phase that is followed by stereotyped, automatisticbehaviors, including twitching of the vibrissae, and Straub-tail.Animals not displaying such behaviors were considered protected. Datawas analyzed by Mann-Whitney U test, with p<0.05 determined to bestatistically significant.

For each time group, the results are expressed as the total number ofanimals protected out of the number of animals tested over time (i.e.,2/4 represents 2 out of 4 mice tested were protected).

TABLE 30 ED50 Biological Response, Methylcellulose Time (Hours) 0.5 TestDose N/F 6 Hz 30 0/8 6 Hz 65 5/8 6 Hz 130 5/8 6 Hz 160  8/16 6 Hz 1907/8

TABLE 31 Time to Peak Effect, Methylcellulose Time (Hours) 0.25 0.5 1 24 6 24 Test Dose N/F N/F N/F N/F N/F N/F N/F 6 Hz 300 1/8 0/8 0/8 0/80/8 0/8 0/8 6 Hz 500 1/8 0/8 0/8 0/8 0/8 0/8 2/8

TABLE 32 ED50 Biological Response, Ethanol:Polyethoxylated castoroil:PBS Test Dose Time N/F 6 Hz 50 0.5 1/8 6 Hz 100 0.5 1/8 6 Hz 130 0.54/8 6 Hz 170 0.5 6/8 6 Hz 200 0.5 8/8 TOX 200 2 0/8 TOX 250 2 4/8 TOX300 2 6/8 TOX 500 2 8/8

TABLE 33 Time to Peak Effect, Ethanol:Polyethoxylated castor oil:PBSTime (Hours) 0.25 0.5 1 2 4 6 8 24 Test Dose N/F N/F N/F N/F N/F N/F N/FN/F TOX 200 — — — 0/8 0/8 — — — TOX 250 — — — 4/8 3/8 — — — TOX 300 — —— 6/8 7/8 4/8 2/8 1/8 TOX 500 0/8 0/8 0/8 8/8 8/8 8/8 — 4/7

As seen in Tables 30 to 33, cannabidiol in both solvents showedcomparable median effective doses that inhibited seizures in 50% ofanimals (ED50s) in the 100 mg/kg range. While cannabidiol dissolved inthe methylcellulose solvent had an ED50 of 103.75 mg/kg (95% ConfidenceInterval of 53.89 mg/kg to 163.84 mg/kg), it showed an ED50 of 121.52mg/kg when dissolved in the 1:1:18 ethanol:polyethoxylated castoroil:PBS solvent (95% Confidence Interval of 87.83 mg/kg to 152.96mg/kg). Based on the toxicity data for the cannabidiol in themethylcellulose solvent, the median toxicity dose where toxicity isobserved in 50% of animals (“TD50”) was determined to exceed 500 mg/kgat 0.5 hours post administration. Diarrhea at 24 hours and 1 death wasreported at 24 hours at 500 mg/kg, the highest dose tested.

The TD50 was determined to be 262.37 mg/kg (95% Confidence Interval of232.64 to 301.78) with cannabidiol dissolved in the 1:1:18ethanol:polyethoxylated castor oil:PBS solvent. Death was reported at 24hours at 300 mg/kg and at 6 and 24 hours for 500 mg/kg with the with the1:1:18 ethanol:polyethoxylated castor oil:PBS solvent.

These results further illustrate that cannabidiol is likely to beeffective in humans for the treatment of epilepsy and other conditions.Further, synthetically synthesized cannabidiol will likely be less toxicthan cannabidiol that is derived from plants and not substantially pure.

Example 11. Maximal Electroshock Seizure and Subcutaneous Metrazol

The maximal electroshock seizure (“MES”) and subcutaneous Metrazol (“scMet”) tests have been the two most widely employed preclinical seizuremodels for the early identification and high through-put screening ofinvestigational anti-seizure drugs. These tests have been extremelyeffective in identifying new anti-seizure drugs that may be useful forthe treatment of human generalized tonic-clonic seizures and generalizedmyoclonic seizures. The MES test provides an indication of CBD's abilityto prevent seizure spread when all neuronal circuits in the brain aremaximally active. The s.c. Met test detects the ability of CBD to raisethe chemoconvulsant-induced seizure threshold of an animal and, thus,protect it from exhibiting a clonic, forebrain seizure.

For the IVIES test, 60 Hz of alternating current is delivered by cornealelectrodes for 0.2 seconds. Supra-maximal seizures are elicited with acurrent intensity five times that necessary to evoke a threshold tonicextension seizure, i.e., 50 mA in mice and 150 mA in rats. A drop ofanesthetic solution, 0.5% tetracaine hydrochloride, is placed on theeyes of each animal just before the corneal electrodes are applied tothe eyes to elicit electrical stimulation. The animals are restrained byhand and released immediately following stimulation to allow observationof the entire seizure. Inhibition of the hind leg tonic extensorcomponent is taken as the endpoint for the MES test.

A dose of Metrazol (85 mg/kg in mice) will induce convulsions in 97% ofmice (CD97). The CD97 dose of Metrazol is injected into a loose fold ofskin in the midline of the neck. The CD97 doses for Metrazol areconfirmed annually in mice. It is administered to mice at a volume of0.01 ml/g body weight. The animals are then placed in isolation cages tominimize stress and continuously monitored for the next 30 min for thepresence or absence of a seizure. An episode of clonic spasms,approximately 3 to 5 seconds, of the fore and/or hind limbs, jaws, orvibrissae is taken as the endpoint. Animals not displaying fore and/orhind limb clonus, jaw chomping, or vibrissae twitching are consideredprotected.

All quantitative in vivo antiseizure/behavioral impairment studies aretypically conducted at the previously determined TPE. Groups of at least8 mice were tested with various doses of cannabidiol until at least twopoints are established between the limits of 100% protection or minimaltoxicity and 0% protection or minimal toxicity. The dose of drugrequired to produce the desired endpoint in 50% of animals (ED50 orTD50) in each test, the 95% confidence interval, the slope of theregression line, and the standard error of the mean (S.E.M.) of theslope is then calculated by probit analysis.

The cannabidiol administered to the mice was substantially pure,synthetically synthesized, cannabidiol which had a purity greater than98%. The cannabidiol was dissolved in 0.5% methylcellulose or a 1:1:18ratio of ethanol:polyethoxylated castor oil:PBS. The maximal electricshock (MES) and subsucanteous Metrazol (“sc MET”) are the most widelyused preclinical seizure models for the early identification andscreening of new antiepileptic drugs.

TABLE 34 ED50 Biological Response, Methylcellulose Test Dose Time N/FMES 200 2 5/8 MES 250 2 4/8 MES 300 2 4/8 MES 350 2 3/8 MES 400 2 3/8MES 450 2 6/8 MES 500 2 8/8 Sc MET 150 2 1/8 Sc MET 200 2 3/8 Sc MET 3002 5/8 Sc MET 360 2 7/8 TOX 500 2 0/8

TABLE 35 Time to Peak Effect, Methylcellulose Time (Hours) 0.25 0.5 1 24 Test Dose N/F N/F N/F N/F N/F MES 300 0/4 1/4 1/4 4/8 2/4 Sc MET 2000/4 0/4 2/8 3/8 — TOX 300 0/4 0/4 0/4 0/4 0/4

TABLE 36 ED50 Biological Response, Ethanol:Polyethoxylated castoroil:PBS Test Dose Time N/F MES 75 2 1/8 MES 95 2 5/8 MES 120 2 7/8 MES150 2 8/8 Sc MET 120 2 0/8 Sc MET 160 2 2/8 Sc MET 220 2 5/8 Sc MET 2602 7/8 TOX 175 2 0/8 TOX 250 2 4/8 TOX 325 2 6/8 TOX 500 2 8/8

TABLE 37 Time to Peak Effect, Ethanol:Polyethoxylated castor oil:PBSTime (Hours) 0.25 0.5 1 2 4 6 8 Test Dose N/F N/F N/F N/F N/F N/F N/FTOX 500 0/8 0/8 0/8 8/8 7/8 7/8 4/8

The ED50 in the MES model for cannabidiol dissolved in themethylcellulose solvent could not be calculated due to a U shaped doseresponse (1/4 protected at 0.5 hr, 1/4 at 1 hr, 4/8 at 2 hr and 2/4 at 4hr). However, the ED50 for cannabidiol dissolved in the 1:1:18ethanol:polyethoxlated castor oil:PBS solvent is 92.21 mg/kg (95%Confidence Interval of 78.4 mg/kg to 104.63 mg/kg).

For the MET model, the ED50 was 241.03 mg/kg (95% Confidence Interval of182.23 to 311.87) for cannabidiol dissolved in the methylcellulosesolvent and 198.51 mg/kg (95% Confidence Interval of 167.76 mg/kg to232.58 mg/kg) for cannabidiol dissolved in the 1:1:18ethanol:polyethoxlated castor oil:PBS solvent. Based on the toxicitydata for cannabidiol dissolved in the methylcellulose solvent the TD50was determined to exceed 500 mg/kg, the highest dose tested.

Myoclonic jerks were reported in at 1 hour with 200 mg/kg dose and at 2hours with 360 mg/kg dose. The TD50 was determined to be 266.76 mg/kg(95% Confidence Interval of 222.28 mg/kg to 317.42 mg/kg) with thecannabidiol dissolved in the 1:1:18 ethanol:polyethoxlated castoroil:PBS solvent.

These results further illustrate that cannabidiol is likely to beeffective in humans for the treatment of epilepsy and other conditions.Further, synthetically synthesized cannabidiol will likely be less toxicthan cannabidiol that is derived from plants and not substantially pure.

1-25. (canceled)
 26. A method of reducing seizure frequency in a subjectwith a refractory epilepsy, comprising administering to the subject acomposition comprising cannabidiol, wherein the cannabidiol has a purityof greater than 98% w/w.
 27. (canceled)
 28. The method of claim 26,wherein the refractory epilepsy is West syndrome.
 29. The method ofclaim 26, wherein the refractory epilepsy is Dravet syndrome.
 30. Themethod of claim 26, wherein the refractory epilepsy is Lennox-Gastautsyndrome.
 31. The method of claim 26, wherein the refractory epilepsycomprises tonic-clonic seizures.
 32. The method of claim 31, wherein thetonic-clonic seizures are generalized tonic-clonic seizures.
 33. Themethod of claim 26, wherein the refractory epilepsy comprises myoclonicseizures.
 34. The method of claim 33, wherein the myoclonic seizures aregeneralized myoclonic seizures.
 35. The method of claim 26, wherein therefractory epilepsy comprises tonic-clonic and myoclonic seizures. 36.The method of claim 26, wherein the subject is a pediatric patient. 37.The method of claim 26, wherein the composition is a liquid solution.38. The method of claim 26, wherein the composition does not containalcohol.
 39. The method of claim 26, wherein the cannabidiol is asynthetically prepared cannabidiol.
 40. The method of claim 26, whereinthe composition comprises about 10 to about 32% w/w of cannabidiol. 41.The method of claim 26, wherein the composition comprises: about 10 toabout 32% w/w of cannabidiol; about 60 to about 95% of a lipid; and anantioxidant.
 42. The method of claim 41, wherein the lipid comprisescaprylic/capric triglycerides.
 43. The method of claim 41, wherein thecomposition comprises about 0.01 to about 1% w/w of an antioxidant, andwherein the antioxidant is alpha-tocopherol.
 44. A method of treating adisease or disorder in a subject, comprising administering to thesubject a composition comprising cannabidiol, wherein the cannabidiolhas a purity of greater than 98% w/w, and wherein the disease ordisorder is characterized by tonic-clonic seizures.
 45. The method ofclaim 44, wherein the disease or disorder is substantially characterizedby tonic-clonic seizures.
 46. The method of claim 44, wherein thetonic-clonic seizures are generalized tonic-clonic seizures.
 47. Themethod of claim 44, wherein the disease or disorder is an epilepsydisorder.
 48. The method of claim 44, wherein the disease or disorder isa refractory epilepsy.
 49. The method of claim 44, wherein the diseaseor disorder is Dravet syndrome.
 50. The method of claim 44, wherein thedisease or disorder is Lennox-Gastaut syndrome.
 51. The method of claim44, wherein the disease or disorder further comprises myoclonicseizures.
 52. The method of claim 51, wherein the myoclonic seizures aregeneralized myoclonic seizures.
 53. The method of claim 44, wherein thesubject is a pediatric patient.
 54. The method of claim 44, wherein thecomposition is a liquid solution.
 55. The method of claim 44, whereinthe composition does not contain alcohol.
 56. The method of claim 44,wherein the cannabidiol is a synthetically prepared cannabidiol.
 57. Themethod of claim 44, wherein the composition comprises about 10 to about32% w/w of cannabidiol.
 58. The method of claim 44, wherein thecomposition comprises: about 10 to about 32% w/w of cannabidiol; about60 to about 95% of a lipid; and an antioxidant.
 59. The method of claim58, wherein the lipid comprises caprylic/capric triglycerides.
 60. Themethod of claim 58, wherein the composition comprises about 0.01 toabout 1% w/w of an antioxidant, and wherein the antioxidant isalpha-tocopherol.
 61. A method of treating a disease or disorder in asubject, comprising administering to the subject a compositioncomprising cannabidiol, wherein the cannabidiol has a purity of greaterthan 98% w/w, and wherein the disease or disorder is characterized bymyoclonic seizures.
 62. The method of claim 61, wherein the disease ordisorder is substantially characterized by myoclonic seizures.
 63. Themethod of claim 61, wherein the myoclonic seizures are generalizedmyoclonic seizures.
 64. The method of claim 61, wherein the disease ordisorder is an epilepsy disorder.
 65. The method of claim 61, whereinthe disease or disorder is a refractory epilepsy.
 66. The method ofclaim 61, wherein the disease or disorder is Dravet syndrome.
 67. Themethod of claim 61, wherein the disease or disorder is Lennox-Gastautsyndrome.
 68. The method of claim 61, wherein the disease or disorderfurther comprises tonic-clonic seizures.
 69. The method of claim 68,wherein the tonic-clonic seizures are generalized tonic-clonic seizures.70. The method of claim 61, wherein the subject is a pediatric patient.71. The method of claim 61, wherein the composition is a liquidsolution.
 72. The method of claim 61, wherein the composition does notcontain alcohol.
 73. The method of claim 61, wherein the cannabidiol isa synthetically prepared cannabidiol.
 74. The method of claim 61,wherein the composition comprises about 10 to about 32% w/w ofcannabidiol.
 75. The method of claim 61, wherein the compositioncomprises: about 10 to about 32% w/w of cannabidiol; about 60 to about95% of a lipid; and an antioxidant.
 76. The method of claim 75, whereinthe lipid comprises caprylic/capric triglycerides.
 77. The method ofclaim 75, wherein the composition comprises about 0.01 to about 1% w/wof an antioxidant, and wherein the antioxidant is alpha-tocopherol.